EP3509640A1 - Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder - Google Patents
Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorderInfo
- Publication number
- EP3509640A1 EP3509640A1 EP17785061.7A EP17785061A EP3509640A1 EP 3509640 A1 EP3509640 A1 EP 3509640A1 EP 17785061 A EP17785061 A EP 17785061A EP 3509640 A1 EP3509640 A1 EP 3509640A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- subject
- tier
- genetic alteration
- genes
- cnv
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- This application relates to diagnosing and treating anorexia nervosa (AN) and binge eating disorders (BED) with a nonselective activator of metabotropic glutamate receptors (mGluRs), for example, in subjects having a genetic alteration in at least one metabotropic glutamate receptor (mGluR) network gene.
- AN anorexia nervosa
- BED binge eating disorders
- mGluRs metabotropic glutamate receptors
- Anorexia nervosa is a complex illness characterized by low body weight and persistent fear of weight gain during periods of growth, resulting in extreme emaciation. Patients with AN usually manifest with symptoms of depression, anxiety, and obsessive- compulsive behaviors that are common features in other neuropsychiatric disorders. [003] Multiple bodies of evidence now suggest the role of genetic influences to AN. Family studies have consistently demonstrated that AN occurs in families and twin studies have revealed the contribution of additive genetic factors to the observed familial aggregation. However, despite many studies, the genetic architecture underlying AN susceptibility remains largely unknown. Few genetic factors have been found to be specific to AN and no single factor has been shown to be necessary or sufficient to express the phenotype. Anorexia Nervosa (AN) has the highest mortality of any psychiatric disorder, and becomes intractable in around 20% of patients, resulting in huge individual cost.
- BED Binge Eating Disorder
- Subjects with BED usually have feelings of a loss of control during the binge, experience shame, distress or guilt afterwards, and often have functional impairment, suicide risk, and a high frequency of co-occurring psychiatric disorders.
- BED may be the most common eating disorder in the United States, with a reported 3.5 % of women and 2 % of men affected. Diagnostic and treatment strategies for AN and BED are urgently needed.
- AN anorexia nervosa
- BED binge eating disorder
- the subject has a genetic alteration, such as a copy number variation (CNV) in at least one gene in the mGluR network.
- CNV copy number variation
- the subject has a genetic alteration in at least one Tier 1, Tier 2, or Tier 3 mGlurR network gene as disclosed herein in Figs. 1-3.
- treating the subject may comprise treating the AN and/or BED, such as alleviating at least one AN and/or BED symptom in the subject.
- the subject is a pediatric or adolescent subject, such as a subject between the ages of 5 and 17, 8 and 17, 5 and 12, 5 and 8, 8 and 12, 12 and 17, 13 and 17, or 13 and 18.
- the subject is an adult.
- the nonselective mGluR activator is fasoracetam, such as fasoracetam monohydrate.
- the fasoracetam is administered at a dose of 50-400 mg, such as 100-400 mg, or 100-200 mg, or 200-400 mg, or 100 mg, or 200 mg, or 300 mg, or 400 mg, and is administered once, twice, or three times daily.
- the fasoracetam is administered at a dose of 100 mg, 200 mg, 300 mg, or 400 mg twice daily, such as 100-200 mg twice daily.
- the activator is administered in combination with another pharmaceutical agent, such as an antidepressant, such as fluoxetine, escitalopram, bupropion, mirtazapine, amitriptyline, imipramine, venlafaxine, sertraline, paroxetine, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, or monoamine oxidase inhibitors; and/or in combination with an anxiolytic, such as barbiturates, pregabalin, or benzodiazepines, including chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazep
- an antidepressant such
- the activator is administered in combination with non- pharmaceutical therapy, such as brain stimulation, for example vagus nerve stimulation, repetitive transcranial magnetic stimulation, magnetic seizure therapy, and/or deep brain stimulation.
- non- pharmaceutical therapy such as brain stimulation, for example vagus nerve stimulation, repetitive transcranial magnetic stimulation, magnetic seizure therapy, and/or deep brain stimulation.
- the activator is administered in an amount or dosage regime shown to be effective to result in a clinical general impression— improvement (CGI-I) score of 1 or 2 after four weeks of treatment and/or an improvement of at least 25%, such as at least 30%, at least 35%, or at least 40%, in an AN rating scale score after four weeks of treatment in a majority of subjects of at least one clinical trial.
- CGI-I clinical general impression— improvement
- the AN may in some cases be deemed treated if at least one symptom of AN is improved in the subject.
- the BED may in some cases be deemed treated if at least one symptom of AN is improved in the subject.
- Also provided herein are methods of treating anorexia nervosa (AN) in a subject comprising administering a therapeutically effective amount of a nonselective
- metabotropic glutamate receptor (mGluR) activator to a subject, thereby treating AN.
- mGluR metabotropic glutamate receptor
- a method of treating AN in a subject comprising administering fasoracetam to the subject at a dose of 50-400 mg, such as 100-400 mg, or 100-200 mg, or 200-400 mg, or 100 mg, or 200 mg, or 300 mg, or 400 mg, wherein the dose is administered once, twice, or three times daily, thereby treating AN.
- the fasoracetam is administered at a dose of 100 mg, 200 mg, 300 mg, or 400 mg twice daily, such as 100-200 mg twice daily.
- the subject has at least one genetic alteration in an mGluR network gene, such as a point mutation, insertion, deletion, or copy number variation (CNV).
- the subject has a genetic alteration in two or more mGluR network genes.
- the genetic alteration is detected by a process comprising a genetic test comprising obtaining a sample from the subject, optionally isolating nucleic acid from the sample, optionally amplifying the nucleic acid, and analyzing the nucleic acid for a genetic alteration in at least one mGluR network gene.
- the treatment method further comprises obtaining results of the genetic test prior to initial
- the genetic test comprises analyzing the nucleic acid for a CNV or SNV in at least 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, or all Tier 1 mGluR network genes (Fig. 1 herein) . In some embodiments, the genetic test comprises analyzing the nucleic acid for a CNV or SNV in at least 5, 10, 20, 30, 50, 100, 150, 175, or all Tier 2 mGluR network genes (Fig. 2). In some embodiments, the method comprises analyzing the nucleic acid for a CNV or SNV in at least 5, 10, 20, 50, 100, 200 300, 400, 500, or all Tier 3 mGluR network genes (Fig. 3).
- the genetic test does not assess CNVs or SNVs in one or more of GRMl, GRM2, GRM3, GRM4, GRM5, GRM6, GRM7 or GRM8.
- the AN subject has a genetic alteration, such as a CNV, in a Tier 1 or Tier 2 mGluR network gene but does not have a genetic alteration, such as a CNV, in a Tier 3 mGluR network gene.
- the invention comprises methods for diagnosing anorexia nervosa (AN) in a subject, comprising:
- BED binge eating disorder
- the genetic alteration is a CNV, such as a deletion or a duplication.
- the genetic alteration may be in at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, or all Tier 1 mGluR network genes.
- the genetic alteration may be in at least 2, 3, 4, 5, 10, 20, 30, 50, 100, 150, 175, or all Tier 2 mGluR network genes.
- the genetic alteration may be in at least 2, 3, 4, 5, 10, 20, 50, 100, 200 300, 400, 500, or all Tier 3 mGluR network genes.
- the subject may have a bingeing and/or purging subtype of AN. In other instances, the subject has the restricting subtype of AN.
- the subject may be a pediatric or adolescent subject between the ages of 5 and 17, 8 and 17, 5 and 12, 5 and 8, 8 and 12, 12 and 17, 13 and 18 or 13 and 17.
- the subject may be an adult patient.
- the method further comprises providing a report comprising suggested treatment(s) for AN and/or BED based upon the genetic alteration(s) identified in the method. In some aspects, the method further comprises prescribing or administering an effective amount of an mGluR activator to the diagnosed patient.
- the diagnosed patient is prescribed, administered, or is already taking one or more antidepressant, anxiolytic or anti-psychotic.
- the antidepressant is fluoxetine, escitalopram, bupropion, mirtazapine, amitriptyline, imipramine, venlafaxine, sertraline, paroxetine, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, or monoamine oxidase inhibitors.
- the anxiolytic is a barbiturate, pregabalin, or
- benzodiazepines including chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, or midazolam.
- the anti-psychotic is olanzapine, quetiapine, aripiprazole or risperidone.
- the invention comprises a method for determining whether a subject is susceptible to developing anorexia nervosa (AN) and/or binge eating disorder (BED), the method comprising:
- the genetic alteration is a CNV.
- the CNV is a deletion or a duplication.
- a system for detecting a genetic alteration related to anorexia nervosa (AN) or binge eating disorder in a subject comprising probes specific for and capable of determining the presence of a genetic alteration in: i) at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, or all Tier 1 mGluR network genes; ii) at least 1, 2, 3, 4, 5, 10, 20, 30, 50, 100, 150, 175, or all Tier 2 mGluR network genes; and/or iii) at least 1, 2, 3, 4, 5, 10, 20, 50, 100, 200 300, 400, 500, or all Tier 3 mGluR network genes.
- the genetic alteration is a point mutation, insertion, deletion, single nucleotide variation (SNV), single nucleotide polymorphism (SNP) or copy number variation (CNV).
- the probes of the system are affixed to a solid support matrix, such as a chip.
- FIG. 1 shows the mGluR network genes included in the Tier 1 gene set. These genes have 2 degrees of protein-protein interaction with mGluR genes (GRM1-8) based on the Cytoscape Human Interactome, which is software for integrating biomolecular interaction networks with high-throughput data (as described in Shannon P (2003) Genome Research 13:2498-2504).
- the Tier 1 gene set includes 76 genes. The exact location for each gene in Tier 1 is listed in both the Human Genome version 18 (hgl 8) and Human Genome version 19 (hgl 9). In addition, the exact gene location plus 500 kilobase (i.e., the range from 500 kilobase before and 500 kilobase after the gene of interest) is listed for hgl 9.
- the start single nucleotide polymorphism (i.e., the SNP located 500 kilobases before the gene of interest) and the EndSNP (i.e., the SNP located 500 kilobases after the gene of interest) are also listed.
- Genes of the mGluRs themselves are noted as "GRM.”
- the expanded regions i.e., 500kg up and down stream) frequently harbor regulatory elements and if impacted by a CNV, can have the same impact on the gene expression and function as a CNV residing in the gene sequence itself.
- FIG. 1 shows the mGluR network genes included in the Tier 2 gene set. These genes have 2 degrees of protein-protein interaction with mGluR genes (GRM1-8) based on the Cytoscape Human Interactome but exclude genes from Tier 1.
- the Tier 2 gene set includes 197 genes. The exact location for each gene in Tier 2 is listed in both the Human Genome version 18 (hgl 8) and Human Genome version 19 (hgl 9) . In addition, the exact gene location plus 500 kilobase (i.e., the range from 500 kilobase before and 500 kilobase after the gene of interest) is listed for hgl 9.
- StartSNP The start single nucleotide polymorphism (StartSNP) (i.e., the SNP located 500 kilobases before the gene of interest) and the EndSNP (i.e., the SNP located 500 kilobases after the gene of interest) in hgl9 are also listed.
- FIG. 3 shows genes within the Tier 3 gene set. Genes with reciprocal gene querying with 2 degrees of protein-protein interaction with mGluR genes based on Cytoscape Human Interactome are included. Genes contained within Tiers 1 and 2 are excluded from Tier 3.
- the Tier 3 gene set includes 599 genes. The exact location for each gene in Tier 3 is listed in both the Human Genome version 18 (hgl 8) and Human Genome version 19 (hgl 9). In addition, the exact gene location plus 500 kilobase (i.e., the range from 500 kilobase before and 500 kilobase after the gene of interest) is listed for hgl9. The StartSNP (i.e., the SNP located 500 kilobases before the gene of interest) and the EndSNP (i.e., the SNP located 500 kilobases after the gene of interest) in hgl 9 are also listed.
- a "mGluR” or metabotropic glutamate receptor refers to one of eight glutamate receptors expressed in neural tissue named mGluRl, mGluR2, mGluR3, mGluR4, mGluR5, mGluR6, mGluR7, and mGluR8. Their genes are abbreviated GRM1 to GRM8.
- the mGluR proteins are G-protein-coupled receptors. They are typically placed into three sub-groups, Group I receptors including mGluRl and mGluR5 are classed as slow excitatory receptors. Group II includes mGluR2 and mGluR3. Group III includes mGluR4, mGluR6, mGluR7, and mGluR8.
- Groups II and III are classed as slow inhibitory receptors.
- the mGluRs are distinguished from the ionotropic GluRs or iGluRs, which are ion channel-associated glutamate receptors and are classed as fast excitatory receptors.
- a "mGluR network gene,” for purposes of this invention, comprises not only the mGluR genes GRMl, GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, and GRM8, but also each of the other genes listed herein in Figs. 1-3 as well as the regions of DNA that regulate the genes listed in Figs 1-3.
- mGluR network proteins are the proteins encoded by the mGluR network genes.
- Tier 1 mGluR network genes are grouped into three subsets: Tier 1, Tier 2, and Tier 3. (See Figs. 1-3.)
- Tier 1 mGluR network genes shown in Fig. 1, comprise 76 genes, including some GRM genes themselves as well as a number of other genes.
- Tier 2 mGluR network genes shown in Fig. 2, comprise 197 genes, and exclude the Tier 1 genes.
- Tiers 1 and 2 together are included in the "primary mGluR network.”
- the "primary network” of mGluR genes also includes the genes 4-Sep, LOC642393, and LOC653098, for a total of 276 genes.
- 4-Sep, LOC642393, and LOC653098 genes There are presently technical difficulties in assessing the 4-Sep, LOC642393, and LOC653098 genes. Thus, they are not included in Tiers 1 and 2, although they are included in the primary network of genes of the present invention.
- the genes of Tier 1 and Tier 2 differ in that alterations in Tier 1 genes had been documented in previous genotyping studies of subjects suffering from mental disorders. ⁇ 0038J Tier 3 mGluR network genes, shown in Fig.
- Tier 3 comprise 599 genes that are in the distal part of the mGluR network based on the merged human interactome provided by the Cytoscape Software (Shannon P et al. (2003) Genome Research 13:2498- 2504), and exclude the Tier 1 and Tier 2 genes.
- the Tier 3 genes are thus part of the "distal mGluR network.”
- the genes LOC285147, LOC147004, and LOC93444 are included in the "distal mGluR network," although they were not assessed in the present study and are not included in Tier 3 due to technical difficulties.
- a "genetic alteration” as used herein means any alteration in the DNA of a gene, or in the DNA regulating a gene, that, for example, may result in a gene product that is functionally changed as compared to a gene product produced from a non-altered DNA.
- a functional change may be differing expression levels (up-regulation or down- regulation) or loss or change in one or more biological activities, for example.
- a genetic alteration includes without limitation, copy number variations (CNVs), single nucleotide variations (SNVs) (also called single nucleotide polymorphisms (SNPs) herein, although a SNP differs from a SNV in that a SNP is found in greater than a certain percentage of the population and therefore is by definition more common than an SNV), frame shift mutations, or any other base pair substitutions, insertions, and deletions.
- CNVs copy number variations
- SNVs single nucleotide variations
- SNPs single nucleotide polymorphisms
- a "copy number variation” or “CNV” is a duplication or deletion of a DNA segment encompassing a gene, genes, segment of a gene, or DNA region regulating a gene, as compared to a reference genome.
- a CNV is determined based on variation from a normal diploid state.
- a CNV represents a copy number change involving a DNA fragment that is 1 kilobase (kb) or larger.
- CNVs described herein do not include those variants that arise from the insertion/deletion of transposable elements (e.g., 6-kb Kpnl repeats).
- the term CNV therefore encompasses terms such as large-scale copy number variants (LCVs; lafrate et al. 2004), copy number polymorphisms (CNPs; Sebat et al. 2004), and intermediate-sized variants (ISVs; Tuzun et al. 2005), but not retrotransposon insertions.
- a "CNV deletion” or “deletion CNV” or similar terms refer to a CNV in which a gene or gene segment is deleted.
- a “CNV duplication” or “duplication CNV” or similar terms refer to a CNV in which a gene or gene segment is present in at least two, and possibly more than two, copies in comparison with the single copy found in a normal reference genome.
- sample refers to a sample from a subject that may be tested, for example, for presence of a CNV in one or more mGluR network proteins, as described herein.
- the sample may comprise cells, and it may comprise body fluids, such as blood, serum, plasma, cerebral spinal fluid, urine, saliva, tears, pleural fluid, and the like.
- the terms "pediatric subject” or “pediatric patient” are used interchangeably to refer to a human less than 18 years of age.
- An “adult patient” or “adult subject” refers to a human 18 years of age or older.
- An “adolescent patient” or “adolescent subject” is typically about 12 to 18, such as 12 to 17 or 13 to 18, years old.
- Anorexia Nervosa (AN)
- AN a psychiatric disorder that may be characterized at least in part by a pathological level of extreme weight loss.
- diagnostic criteria for AN include: 1) restricting food intake— eating less than needed to maintain a body weight that's at or above the minimum normal weight for your age and height; 2) fear of gaining weight: intense fear of gaining weight or becoming fat, or persistent behavior that interferes with weight gain, such as vomiting or using laxatives, even though you're underweight; and 3) problems with body image: denying the seriousness of having a low body weight, connecting your weight to your self-worth, or having a distorted image of your appearance or shape.
- Physical signs and symptoms of AN can include: extreme weight loss; a thin appearance; abnormal blood counts; fatigue; insomnia; dizziness or fainting; bluish discoloration of the fingers; hair that thins, breaks or falls out; soft, downy hair covering the body; absence of menstruation; constipation; dry or yellowish skin; intolerance of cold; irregular heart rhythms; low blood pressure; dehydration; osteoporosis; and swelling of arms or legs.
- Emotional and behavioral symptoms of AN can include severely restricting food intake through dieting or fasting and may include excessive exercise, and/or bingeing and self-induced vomiting to get rid of the food and may include use of laxatives, enemas, diet aids or herbal products.
- Other emotional and behavioral signs and symptoms related to anorexia may include: preoccupation with food; refusal to eat; denial of hunger; fear of gaining weight; lying about how much food has been eaten; flat mood (lack of emotion); social withdrawal; irritability; reduced interest in sex; depressed mood; and thoughts of suicide.
- Additional signs and symptoms that can be indicative of AN can include: skipping meals; making excuses for not eating; eating only a few certain "safe" foods, usually those low in fat and calories; adopting rigid meal or eating rituals, such as spitting food out after chewing; cooking elaborate meals for others but refusing to eat; repeated weighing or measuring of themselves; frequent checking in the mirror for perceived flaws;
- the restricting subtype refers to AN subjects in which in which weight loss is accomplished primarily through dieting, fasting, or excessive exercise. During the current episode of AN, these individuals have not regularly engaged in binge eating or purging.
- the other subtype of AN is the binge- eating/purging subtype. This subtype refers to AN subjects that have engaged in binge eating or purging (or both) during the current episode of AN.
- the treatment methods of the invention may treat any of the above-mentioned AN symptoms. Improvement in any or all of the above-mentioned symptoms is indicative of successful treatment of AN.
- antidepressants such as serotonin selective uptake inhibitors, e.g. fluoxetine, sertraline, and citalopram, as well as clonidine and guanfacine.
- antidepressants such as serotonin selective uptake inhibitors, e.g. fluoxetine, sertraline, and citalopram, as well as clonidine and guanfacine.
- BED Binge Eating Disorder
- DSM-5 Diagnostic and Statistical Manual of Mental Disorders
- binge eating which is characterized by eating in a discrete period of time (for example, within any 2-hour period), and eating an amount of food that is larger than most people would eat in a similar period of time under similar circumstances; or
- a binge-eating episode is associated with three (or more) of the following: eating much more rapidly than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of feeling embarrassed by how much one is eating, and feeling disgusted with oneself, depressed, or very guilty afterwards.
- the subject is typically distressed regarding binge eating being present.
- the binge eating occurs, on average, at least once a week for three months.
- Binge Eating Disorder is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake
- the treatment methods of the invention may treat any of the above-mentioned BED symptoms. Improvement in any or all of the above-mentioned BED symptoms is indicative of successful treatment.
- the Binge Eating Scale (BES) is a 16-item questionnaire that assesses the presence of certain binge eating behaviors, and is used to diagnose BED, as well as to monitor progress throughout treatment.
- the mGluR network genes are 16-item questionnaire that assesses the presence of certain binge eating behaviors, and is used to diagnose BED, as well as to monitor progress throughout treatment.
- the mGluR network genes are 16-item questionnaire that assesses the presence of certain binge eating behaviors, and is used to diagnose BED, as well as to monitor progress throughout treatment.
- the mGluR network genes are 16-item questionnaire that assesses the presence of certain binge eating behaviors, and is used to diagnose BED, as well as to monitor progress throughout treatment.
- the mGluR network genes are 16-item questionnaire that assesses the presence of certain binge eating behaviors, and is used to diagnose BED, as well as to monitor progress throughout treatment.
- the mGluR network genes are 16-item questionnaire that assesses the presence of certain bin
- AN and BED patients may be evaluated prior to treatment for a genetic alteration in one or more of the Tier 1, 2, and/or 3 mGluR network genes, such as single gene or a panel of such genes.
- the genetic alteration is a copy number variation (CNV), resulting from a duplication or other multiplication of one or both copies of the gene or a deletion of one or both copies of the gene.
- CNV deletion or duplication can alter the expression of a resulting gene product contained within the CNV because of the change in copy number of this gene, and may therefore contribute to a disease phenotype.
- a CNV deletion or duplication may also have no effect on relative expression of gene products in any tissue (see Hennchsen CN et al. (2009) Human Molecular Genetics, 2009, Vol. 18(1 ):R1 -K8).
- a CNV deletion or duplication may also affect the expression of genes located in the vicinity of the CNV, such that expression of genes outside of the actual CNV may also be affected.
- a CNV can also influence gene expression through perturbation of transcript structure; for example, a duplication CNV may lead to an increase in copy number but may actually lead to a decrease in gene product due to interference with normal transcription.
- AN and BED patients who have at least one genetic alteration, such as at least one CNV in an mGluR network gene, such as in a Tierl, Tier2, and/or Tier3 gene as shown in Figs. 1-3 are treated with an mGluR activator such as fasoracetam.
- gene sets or panels of mGluR network genes are used for analyzing samples from patients with suspected AN or BED.
- the presence of genetic alterations such as CNV duplications or deletions within these gene sets or panels is determined.
- genetic alterations such as CNVs in the Tier 1 genes shown in Fig. 1 are determined.
- a panel of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, or all of the Tier 1 genes is evaluated for the presence of genetic alterations such as CNVs.
- any individual, specific Tier 1 genes may also be excluded from the panel. For instance, in some embodiments, one or more of the GRM 1-8 genes are not included in the panel.
- the Tier 2 genes as shown in Figure 2 are analyzed for the presence of genetic alterations such as CNVs, optionally in addition to evaluation of the above Tier 1 evaluations or in addition to evaluations of subsets of the Tier 1 genes as described above.
- at least 50 Tier 2 genes are evaluated, while in some embodiments, at least 1, 2, 3, 4, 5, 10, 20, 30, 50, 100, 150, or all of the Tier 2 genes are evaluated.
- Individual, specific Tier 2 genes may be excluded from the gene set for evaluation in some embodiments.
- Tier 3 genes shown in Figure 3 are evaluated for genetic alterations such as CNVs, optionally in addition to evaluation of the above Tier 1 and/or Tier 2 evaluations or in addition to evaluations of subsets of the Tier 1 and/or Tier 2 genes as described above.
- Tier 3 genes are considered a wide range of potential interactors with the mGluR network, and genes contained within Tier 3 are not contained in Tier 1 and Tier 2.
- at least 1, 2, 3, 4, 5, 10, 20, 50, 100, 200, 300, 400, 500 or all of the Tier 3 genes are included in a panel to evaluate genetic alterations. Evaluation of Genetic Alterations in mGluR network Genes
- Any biological sample may be used to determine the presence or absence of mGluR network gene alterations, including, but not limited to, blood, urine, serum, gastric lavage, CNS fluid, any type of cell (such as brain cells, white blood cells, mononuclear cells) or body tissue. Any biological source material whereby DNA can be extracted may be used to determine the presence or absence of mGluR network gene alterations. Samples may be freshly collected, or samples may have been previously collected for any use/purpose and stored until the time of testing for genetic alterations.
- DNA that was previously purified for a different purpose may also be used.
- SNV Single Nucleotide Variation
- SNP Single Nucleotide Polymorphism
- Determining whether a patient has a genetic alteration, such as a CNV, in an mGluR network gene may be done by SNV/SNP Genotyping, using a SNV/SNP genotyping array such as those commercially available from Illumina or Affymetrix.
- SNVs can be determined by hybridizing complementary DNA probes to the SNV site.
- a wide range of platforms can be used with SNV genotyping tools to accommodate varying sample throughputs, multiplexing capabilities, and chemistries.
- SNV arrays hundreds of thousands of probes are arrayed on a small chip, such that many SNVs can be interrogated simultaneously when target DNA is processed on the chip.
- specific SNV alleles can be determined.
- Use of arrays for SNV genotyping allows the large-scale interrogation of SNVs.
- a computer program can be used to manipulate the SNV data to arrive at CNV data.
- PennCNV or a similar program can then be used to detect signal patterns across the genome and identify consecutive genetic markers with copy number changes.
- PennCNV allows for kilobase-resolution detection of CNVs.
- the SNV genotyping data is compared with the behavior of normal diploid DNA.
- the software uses SNV genotyping data to determine the signal intensity data and SNV allelic ratio distribution and to then use these data to determine when there is deviation from the normal diploid condition of DNA that indicates a CNV. This is done in part by using the log R Ratio (LRR), which is a normalized measure of the total signal intensity for the two alleles of the SNV (Wang 2008). If the software detects regions of contiguous SNVs with intensity (LRR) trending below 0, this indicates a CNV deletion. If the software instead detects regions of contiguous SNVs with intensity (LRR) trending above 0, this indicates a CNV duplication.
- LRR log R Ratio
- the software also uses B allele frequency (BAF), a normalized measure of the allelic intensity ratio of two alleles that changes when alleles are lost or gained as with a CNV deletion or duplication.
- BAF B allele frequency
- a CNV deletion is indicated by both a decrease in LRR values and a lack of heterozygotes in BAF values.
- a CNV duplication is indicated by both an increase in LRR values and a splitting of the heterozygous genotype BAF clusters into two distinct clusters.
- the software automates the calculation of LRR and BAF to detect CNV deletions and duplications for whole- genome SNV data. The simultaneous analysis of intensity and genotype data accurately defines the normal diploid state and determines CNVs.
- Array platforms such as those from Illumina, Affymetrix, and Agilent may be used in SNV Genotyping. Custom arrays may also be designed and used based on the data described herein.
- Comparative genomic hybridization is another method that may be used to evaluate genetic alterations such as CNVs.
- CGH is a molecular cytogenetic method for analyzing genetic alterations such as CNVs in comparison to a reference sample using competitive fluorescence in situ hybridization (FISH).
- FISH competitive fluorescence in situ hybridization
- DNA is isolated from a patient and a reference source and independently labeled with fluorescent molecules (i.e., fluorophores) after denaturation of the DNA.
- Hybridization of the fluorophores to the resultant samples are compared along the length of each chromosome to identify chromosomal differences between the two sources.
- a mismatch of colors indicates a gain or loss of material in the test sample in a specific region, while a match of the colors indicates no difference in genetic alterations such as copy number between the test and reference samples at a particular region.
- Whole genome sequencing, whole exome sequencing, or targeted sequencing may also be used to analyze genetic alterations such as CNVs.
- Whole genome sequencing also known as full genome sequencing, complete genome sequencing, or entire genome sequencing
- Whole genome sequencing involves sequencing of the full genome of a species, including genes that do or do not code for proteins.
- Whole exome sequencing in contrast, is sequencing of only the protein-coding genes in the genome (approximately 1% of the genome).
- Targeted sequencing involves sequencing of only selected parts of the genome.
- NGS next-generation sequencing
- Methods for whole exome sequencing include polymerase chain reaction methods, NGS methods, molecular inversion probes, hybrid capture using microarrays, in-solution capture, and classical Sanger sequencing.
- Targeted sequencing allows for providing sequence data for specific genes rather than whole genomes and can use any of the techniques used for other types of sequencing, including specialized microarrays containing materials for sequencing genes of interest.
- Proprietary methodologies such as those from BioNano or OpGen, using genome mapping technology can also be used to evaluate genetic alterations such as CNVs.
- Standard molecular biology methodologies such as quantitative polymerase chain reaction (PCR), droplet PCR, and TaqMan probes (i.e., hydrolysis probes designed to increase the specificity of quantitative PCR) can be used to assess genetic alterations such as CNVs.
- Fluorescent in situ hybridization (FISH) probes may also be used to evaluate genetic alterations such as CNVs.
- FISH fluorescent in situ hybridization
- a subject with AN is treated with a nonselective mGluR activator.
- a subject with BED is treated with a nonselective mGluR activator.
- a subject with AN and BED is treated with a nonselective mGluR activator.
- the terms "pediatric subject” or “pediatric patient” are used interchangeably to refer to a human less than 18 years of age. In some embodiments, the pediatric subject may be between 6 and 17 years old, such as between 12 and 17 years old or between 6 and 12 years old.
- the terms "adult subject” or “adult patient” refer to a human of at least 18 years of age.
- An “adolescent” subject for example, may be between 12 and 18, such as 12-17, 12-18, 13-17, or 13-18 years old.
- treatment covers any administration or application of a therapeutic for disease in a subject, and includes inhibiting the disease, arresting its development, relieving one or more symptoms of the disease, or preventing reoccurrence of one or more symptoms of the disease.
- treatment of AN subjects may comprise alleviating neurobehavioral, neuropsychiatric and neurodevelopmental symptoms associated with AN.
- symptoms include but are not limited to, improvements in increases in BMI, resumed menstruation, the resting energy expenditure (REE; measured in kilocalories per kilogram per day) returning to normal from heightened levels; improvements in eating attitudes, improvements in depression, and/or improvements in eating-related family conflict.
- Treatment of BED subjects may, for example, comprise lessening of the frequency of recurrent episodes of binge eating, lessening of the frequency of episodes where the subject eats an amount of food that is larger than most people would eat in a similar period of time under similar circumstances, an improvement in the feeling of control when eating, slower eating, feeling less uncomfortable after eating, increase in the frequency of eating in public, and a lessening of a feeling of disgust with oneself, depression, or guilt after eating.
- the mGluR proteins are typically placed into three sub-groups, group I receptors including mGluRl and mGluR5 are classed as slow excitatory receptors.
- Group II includes mGluR2 and mGluR3.
- Group III includes mGluR4, mGluR6, mGluR7, and mGluR8. Groups II and III are classed as slow inhibitory receptors.
- the mGluRs are distinguished from the ionotropic GluRs or iGluRs, which are ion channel-associated glutamate receptors and are classed as fast excitatory receptors.
- a "nonselective activator of mGluRs” refers to a molecule that agonizes mGluRs from more than one of the group I, II, and III categories. Thus, a nonselective activator of mGluRs may provide for a general stimulation of the mGluR networks. This is in contrast to specific mGluR activators that may only significantly agonize a single mGluR, such as mGluR5, for example.
- Fasoracetam is a nootropic (i.e., cognitive-enhancing) drug that can stimulate both group I and group II/III mGluRs in in vitro studies. ⁇ See HirouchiM, et al. (2000) European Journal of Pharmacology 387:9-17.) Fasoracetam may stimulate adenylate cyclase activity through activation of group I mGluRs, while it may also inhibit adenylate cyclase activity by stimulating group II and III mGluRs.
- Fasoracetam has been observed to be highly bioavailable (79%-97%) with a half-life of 5- 6.5 hours in prior human studies ⁇ see Mal kh AG, et al. (2010) Drugs 70(3):287-312).
- Fasoracetam is a member of the racetam family of chemicals that share a five-carbon
- fasoracetam The structure of fasoracetam is: .
- fasoracetam encompasses pharmaceutically acceptable hydrates and any solid state, amorphous, or crystalline forms of the fasoracetam molecule.
- fasoracetam herein includes forms such as fasoracetam: fasoracetam monohydrate.
- fasoracetam is also known as C-NS-105, NS105, NS-105, and LAM-105.
- Fasoracetam has been previously studied in Phase I-III clinical trials in dementia- related cognitive impairment but did not show sufficient efficacy in dementia in Phase III trials. These trials demonstrated that fasoracetam was generally safe and well tolerated for those indications. Phase III data indicated that fasoracetam showed beneficial effects on psychiatric symptoms in cerebral infarct patients and adult dementia patients with cerebrovascular diseases. Another racetam compound, piracetam, has been tested in pediatric ADHD subjects and found to actually increase ADHD symptoms in those subjects compared to a placebo control. ⁇ See Akhundian, J., Egyptian J. Pediatrics 2001,
- fasoracetam may be administered as fasoracetam monohydrate (fasoracetam) .
- fasoracetam may be administered by mouth (i.e., per os).
- fasoracetam may be administered as capsules, tablets, caplets, oral solutions, and oral suspensions.
- fasoracetam capsules or tablets or the like may contain 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 600 mg, or 800 mg of fasoracetam, or any range bounded by two of the above numbers.
- fasoracetam at any of the 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg dosages above may be administered once daily, twice, or three times daily.
- the total daily dose of fasoracetam may be 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg given once-daily or 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg given twice- daily.
- fasoracetam dosing may be adjusted using a series of dose escalations.
- pharmacokinetic data on drug level or clinical response are used to determine changes in dosing.
- dose escalation of fasoracetam is not used.
- subjects are treated at a dose of fasoracetam expected to be clinically efficacious without a dose-escalation protocol.
- the nonselective activator of mGluR network proteins is used in combination with other agents for the treatment of AN or BED. In some embodiments, it is used in combination with current AN and/ or BED medications, such as antidepressants or antipsychotics.
- the activator may be used in combination with an anxiolytic (such as barbiturates, pregabalin, or benzodiazepines, including
- antidepressents such as serotonin selective uptake inhibitors, e.g. fluoxetine, sertraline, and citalopram.
- Antidepressants include, for example, fluoxetine, escitalopram, bupropion, mirtazapine, amitriptyline, imipramine, venlafaxine, sertraline, paroxetine, or other compounds in the classes of tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, monoamine oxidase inhibitors, or other drugs approved for the use of depression.
- the other agent may be an anti-psychotic drug, such as olanzapine, clozapine, quetiapine, haloperidol, aripiprazole or risperidone.
- fasoracetam may be used in combination with a non- pharmacologic treatment, such as psychotherapy or brain stimulation therapies.
- a non- pharmacologic treatment such as psychotherapy or brain stimulation therapies.
- the patient is further treated with brain stimulation, which may be vagus nerve stimulation, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, or any other therapies involving modulation of brain function by electricity, magnets, or implants.
- BES Binge Eating Scale
- Eating Disorder Examination EDE
- YBS- EDS Yale-Brown-Cornell Eating Disorder Scale
- EDI Eating Disorder Inventory
- Secondary efficacy measures include a Hamilton score on the Hamilton Depression Rating Scale and the Leeds-Oxford food preference task: "implicit wanting" of low versus high calorie foods, as indexed by reaction times to high versus low calorie food pictures.
- the Eating Disorder Examination Interview was devised in 1987 and is a semi- structured interview conducted by a clinical practioner in the assessment of an eating disorder.
- the EDE is rated through the use of four subscales and a global score.
- the four subscales are: 1) restraint; 2) eating concern; 3) shape concern; and 4) weight concern.
- the questions concern the frequency in which the patient engages in behaviors indicative of an eating disorder over a 28-day period.
- the test is scored on a 7-point scale from 0-6. With a zero score indicating not having engaged in the questioned behavior.
- the Yale-Brown-Cornell Eating Disorder Scale (YBC-EDS) does not limit assessment to a particular set of eating-related concerns or behaviors. Rather, it assesses the severity of illness associated with an individual's unique symptomatology. In particular, the test is an interview which characterizes and quantifies preoccupations and rituals associated with eating disorders.
- the Eating Disorder Inventory (EDI) test is a self-report measure of symptoms frequently related to anorexia nervosa and other eating disorders.
- the Eating disorder inventory (EDI) comprises 64 questions, divided into eight subscales. Each question is on a 6-point scale (ranging from “always" to "never"), rated 0-3. The score for each sub- scale is then summed.
- the 8 subscale scores on the original EDI are:
- IA Interoceptive awareness
- Impulse Regulation shows the ability to regulate impulsive behavior, especially the binge behavior
- Other scoring systems used in AN assessment include the Ease of Eating Scale (EOES); the Color A Person Test (CAPT); Body Image Software (BIS) testing either Average Distortion, or Average Desired Thinness; a change in ratings of anxiety symptoms on the Multidimensional Anxiety Scale for Children (MASC); and changes in serum leptin or prolactin levels.
- the Ease of Eating Scale is a 14-item scale which measures Food avoidance behaviors (FABs).
- the scale is rated by staff observing a subject eating a meal or snack. A score of zero is normal eating behavior. The maximum score is 28. Higher scores indicate more food avoidance behaviors, such as taking small bites, taking > 30 seconds between bites (slow eating), etc.
- Color A Person Test Subjects color an outlined image of a body to indicate body dissatisfaction (red (5): very dissatisfied, yellow: dissatisfied, black: neutral, green: satisfied, blue: very satisfied (1)). The outline is divided into 16 sections for scoring. Total CAPT scores are calculated by adding the total score and dividing by 16. Score range is 1-5. Lower scores indicate less body dissatisfaction.
- Body Image Software Average Distortion - The subject adjusts a digital image of themselves on the computer using the direction to "adjust their image to how they see themselves right now.” This determines their perception of their current image. Accuracy is measured by a smaller score between desired image and actual image. There are no identifiable minimum /maximum values as there would be in a questionnaire scale. There are no subscales.
- Body Image Software Average Desired Thinness - The subject adjusts a digital image of themselves on the computer to "their desired image.” The BIS program calculates the difference between their actual image, and how much they have adjusted the image to represent their “desired image.” Accuracy is measured by a smaller score between desired image and actual image. There are no identifiable
- the Multidimensional Anxiety Scale for Children is a self-report measure completed by the subject that measures anxiety symptoms. Higher scores indicate greater anxiety. A score of over 50 is significant for anxiety.
- Leptin is a protein hormone produced by adipocytes that provides information about body fat content. AN patients have decreased serum leptin levels compared to healthy control subjects, and a positive correlation has been found for body mass index and leptin levels in AN patients.
- Change in Prolactin Levels Men and non-pregnant women will normally have only small amounts of prolactin in their blood. A high level of prolactin
- hypoprolactinemia may be seen in AN patients.
- CGI-S and CGI-I Clinical global impressions severity/improvement
- Some embodiments of methods of treatment herein refer to administering to a subject an amount of a nonselective mGluR network activator effective to reduce an EDE Global Score, a YBC-EDS Scale Score, or an EDI Score by at least 25%, such as at least 30% or at least 40%, after a certain period of treatment, such as 4 weeks, in a majority of clinical trial subjects.
- the amount for administration may, for example, be selected based on clinical results showing that the amount led to such a result in a majority of previously assessed clinical patients. For example, if a subject to be treated is a pediatric subject, the treatment amount may be selected on the basis of achieving such results in a majority of patients in a clinical trial of pediatric subjects.
- the Clinical Global Impression Scale is a widely-used assessment instrument in psychiatry and is a common secondary efficacy measure for AN clinical trials.
- the CGI scale generally asks the clinician to provide a global assessment of the patient's function, symptoms, and adverse events based on the clinician's experience with AN patients.
- the CGI scale has two component measurements, CGI-S (clinical global impression - severity; a measure of disease severity) and CGI-I (clinical global impression — improvement; a measure of improvement in symptoms). Both scales range from 1 to 7.
- the CGI-S scale ranges from 1 (normal) to 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill) and 7 (among the most extremely impaired).
- the CGI-I scale ranges from 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), to 7 (very much worse).
- subjects with a CGI-I score of 1 or 2 compared to a base-line or placebo level are considered responders to a treatment regimen.
- a responder to a drug regimen may show a reduction in EDE Global Score, a YBC-EDS Score, or an EDI Score of at least 25%, such as at least 30%, at least 35%, or at least 40%, as well as a CGI-I score of either 1 or 2 after a certain period of treatment, such as 4 weeks.
- the amount of nonselective mGluR activator administered to a subject is chosen based on that amount's ability to give a CGI-I score of 1 or 2 in a majority of subjects in a clinical trial, for example a clinical trial of similar subjects.
- a particular amount of activator gives a CGI-I score of 1 or 2 in a majority of patients in the trial after a particular period of time
- that amount may be chosen to give to another pediatric subject as a treatment dose.
- the invention comprises articles of manufacture that may be used in the methods and treatments described herein.
- the manufacture is a solid support or microarray for use in detecting genetic alterations in some or all of the mGluR network genes listed in Figs. 1-3 (i.e., Tiers 1-3).
- genes contained in multiple Tiers are assessed within the same solid support or microarray.
- certain mGluR network genes are excluded.
- the GRM genes are excluded.
- a solid support or microarray such as on a chip, is used that contains appropriate probes for determining the presence of genetic alterations in 10, 20, 30, 40, 50, 60, 70 or all of the Tier 1 genes.
- the solid support or microarray may also include appropriate probes for determining the presence of genetic alterations in at least 10, 20, 30, 50, 100, 150, or all of the Tier 2 genes.
- it may further include appropriate probes for determining the presence of genetic alterations in at least 10, 20, 50, 100, 200, 300, 400, 500 or all of the Tier 3 genes.
- a solid support, microarray, or chip may be used to determine the presence of genetic alterations such as CNVs or SNVs in the Tier 1, Tier 1+2, or Tier 1 +2+3 mGluR gene networks as part of a method of treating an AN or BED patient.
- the manufacture is a set of probes for mGluR network genes of interest from Tiers 1, 2, and/or 3.
- the probes are labelled. The labels may be non-natural.
- sets of probes may be
- probes may be manufactured for determining the presence of genetic alterations in 10, 20, 30, 40, 50, 60, 70 or all of the Tier 1 genes.
- probes may be manufactured for determining the presence of genetic alterations in at least 10, 20, 30, 50, 100, 150, or all of the Tier 2 genes.
- probes may further include those for determining the presence of genetic alterations in at least 10, 20, 50, 100, 200, 300, 400, 500 or all of the Tier 3 genes.
- These various probe sets may be used in methods of determining the presence of genetic alterations, such as CNVs and SNVs in the Tier 1, Tier 1+2, or Tier 1 +2+3 mGluR gene networks as part of a method of treating an AN or BED patient Example 1. Analysis of Genetic Alterations in the mGluR Network of Genes in Anorexia Nervosa and Binge Eating Disorder
- Table 1 Total number of subjects among 1,040 children with AN who are mGluR mutation positive.
- Table 2 shows data of representative CNVs from subjects with AN wherein a Tier 1 mGluR network gene was located within, or in the vicinity of, a CNV in the patient's sample.
- CNVs can lead to structural changes that affect the transcription of genes located outside of, but in the vicinity of, the CNV.
- mGluR network genes within one of the Tiers that were located within 500,000 base pairs of a CNV were included in the analysis.
- an mGluR network gene is contained in close proximity to a CNV but not within it, this is presented with a "distance from gene” value of greater than 0.
- Table 2 lists the chromosome wherein the CNV was located, with its start and stop location in relation to the Human Genome version 19 (hgl9).
- the number of SNVs (SNPs) located within the CNV is noted as “Num SNP,” and the length of the CNV is noted in base pairs.
- the StartSNP and EndSNP of the CNV are also provided.
- the "State, CN” column indicates the copy number resulting from the CNV.
- normal human DNA i.e. with no CNV
- CNVs with a "State, CN” of 0 or 1 indicate a copy number deletion.
- CNVs with a "State, CN” of three or greater indicate a copy number duplication.
- the confidence value indicates the relative confidence that the call of the CNV is correct. All CNVs included in this analysis had a positive confidence value, indicating a high likelihood that the CNV call is correct. A value of 15 or greater was seen for most CNVs and is considered extremely high confidence in the CNV call based on qPCR and Taqman genotyping validation.
- the "mGluR gene” column lists the specific mGluR network gene within Tier 1 contained within the listed CNV. Table 1 is sorted to show all of the CNVs that included a given Tier 1 mGluR network gene. Some Tier 1 genes may be represented in multiple CNVs from different patients in the study, leading to multiple rows for those particular mGluR network genes. Some Tier 1 genes may not have been represented in a CNV from this particular patient population.
- Table 3 shows data from specific CNVs that contained a Tier 1 or Tier 2 mGluR network gene.
- the organization of Table 2 follows that of Table 1.
- the "mGluR gene” column lists the specific mGluR network gene within Tier 1 or Tier 2 contained within the listed CNV.
- Table 2 is sorted to show all of the CNVs that included a given Tier 1 or Tier 2 mGluR network gene.
- Some Tier 1 or Tier 2 genes may be represented in multiple CNVs from different patients in the study, leading to multiple rows for those particular genes. Some Tier 1 or Tier 2 genes may not have been represented in a CNV from this particular patient population.
- Table 4 shows data from specific CNVs that contained a Tier 1, 2, or 3 mGluR network gene.
- the organization of Table 3 follows that of Tables 1 and 2.
- the "mGluR gene” column lists the specific mGluR network gene within Tier 1, Tier 2, or Tier 3 contained within the listed CNV.
- Table 3 is sorted to show all the CNVs that included a given Tier 1, 2, or 3 mGluR network gene.
- Some Tier 1, 2, or 3 genes may be represented in multiple CNVs from different patients in the study, leading to multiple rows for those particular mGluR network genes.
- Some Tier 1, 2, or 3 genes may not have been represented in a CNV from this particular patient population.
- Table 6 is a summary table that summarizes the information from Tables 2-4.
- Example 2 Treatment of Anorexia Nervosa and Binge Eating Disorder with CNVs in mGluR network Genes with fasoracetam (fasoracetam monohydrate) jOO 22]
- fasoracetam fasoracetam monohydrate
- adolescent subjects between the ages of 12 and 17 previously diagnosed with ADHD.
- Each of the study subjects in this clinical trial had one or more CNV in an mGluR network gene.
- Fasoracetam monohydrate successfully treated these ADHD patients. None of the patients in the ADHD clinical study had a formal diagnosis of AN. However, appetite was observed to be improved in the children tested, suggesting that fasoracetam may have beneficial effects in AN.
- a clinical trial will be initiated to investigate the safety, pharmacokinetics and efficacy of fasoracetam in subjects between the ages of 12 and 21 previously diagnosed with AN who also have at least one genetic alteration in an mGluR network gene.
- j ' OO ' i 24 j The study will include at least 30 subjects who are between ages 12 and 21, of any ancestry or race, diagnosed with anorexia nervosa (AN) as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5 th Ed (DSM-5). Subjects will be genotyped and included in the trial if they possess at least one genetic alteration in the form of at least one copy number variation (deletion or duplication) in a mGluR network gene.
- Exclusion criteria comprises subjects suffering from a clinically significant illness, either mental or physical, that, in the investigator's opinion, might confound the results of the study or that might prevent them from completing the study, subjects that are pregnant or nursing, subjects that test positive for illicit drugs of that have a history of drug abuse, subjects that consume alcoholic beverages, or subjects for which the investigator is otherwise concerned regarding their compliance or suitability.
- Fasoracetam capsules of either 50 mg or 200 mg comprising fasoracetam monohydrate as active ingredient and placebo capsules comprising microcellulose will be used for the study.
- the design of the trial is a phone screening (1 day), enrollment phase (1 to 2 days), a wash-out phase for subjects currently on medications prescribed for AN (1-14 days), pharmacokinetic (PK) assessment (2 days), followed by a dose-escalation phase (35 days) and a follow-up phone visit approximately four weeks after the last dose, for a maximum of 127 days. All medications prescribed for AN will be discontinued during the wash-out phase prior to the study. No new AN medication will be started during the study.
- the dose-escalation phase of the trial runs over a 5-week period. During week 1, all subjects are administered placebo capsules twice daily. After one week of placebo treatment, patients are started on 50 mg b.i.d. fasoracetam for 1 week. If safety and responsiveness data from prior dose level of fasoracetam indicates it was appropriate, subjects are then escalated to the next higher dose (100, 200, or 400 mg). Subjects who show tolerance to the 50 mg b.i.d. dose as well as response to the drug are to be maintained at that level for the remaining 3 weeks of the trial. Subjects who show tolerance but lack of response or partial response to the 50 mg b.i.d.
- subjects who show tolerance at 100 mg but lack of response or partial response are to be moved up to the 200 mg dose the following week while those who show both tolerance and response at 100 mg are to be kept at 100 mg bid for the remainder of the trial.
- subjects moved up to the 200 mg dose who showed both tolerance and response are to be kept at 200 mg for the final week of the trial while those showing tolerance but lack of response or partial response are moved to a 400 mg dose for the final week.
- subjects visit the clinic again at the end of each week to be administered the efficacy tests, and to be given a general physical examination including vital signs and weight, blood and urine sampling, and a pregnancy test for female subjects.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Analytical Chemistry (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662384686P | 2016-09-07 | 2016-09-07 | |
PCT/US2017/050228 WO2018048868A1 (en) | 2016-09-07 | 2017-09-06 | Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3509640A1 true EP3509640A1 (en) | 2019-07-17 |
Family
ID=60120122
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17785061.7A Withdrawn EP3509640A1 (en) | 2016-09-07 | 2017-09-06 | Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder |
Country Status (4)
Country | Link |
---|---|
US (2) | US10918632B2 (en) |
EP (1) | EP3509640A1 (en) |
CA (1) | CA3035971A1 (en) |
WO (1) | WO2018048868A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10918632B2 (en) * | 2016-09-07 | 2021-02-16 | The Children's Hospital Of Philadelphia | Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder |
CA3088970A1 (en) | 2018-01-18 | 2019-07-25 | The Children's Hospital Of Philadelphia | Fasoracetam crystalline forms |
WO2019143824A1 (en) | 2018-01-18 | 2019-07-25 | Aevi Genomic Medicine, Inc. | Solid forms of fasoracetam |
US11413084B2 (en) * | 2018-07-03 | 2022-08-16 | Medtronic Ardian Luxembourg S.A.R.L. | Methods for treating eating disorders in patients via renal neuromodulation |
CN112458160B (en) * | 2020-08-27 | 2022-05-31 | 中国人民解放军军事科学院军事医学研究院 | Method and kit for detecting polymorphism of 11q14.2 region related to severe coronavirus pneumonia, and application of method and kit |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9420784D0 (en) * | 1994-10-14 | 1994-11-30 | Glaxo Group Ltd | Medicaments |
EP1809620B1 (en) * | 2004-11-04 | 2010-12-29 | Addex Pharma SA | Novel tetrazole derivatives as positive allosteric modulators of metabotropic glutamate receptors |
AU2010332819B2 (en) | 2009-12-18 | 2014-02-27 | Janssen Pharmaceutica Nv | Bicyclic thiazoles as allosteric modulators of mGluR5 receptors |
JO3367B1 (en) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
DK3347016T3 (en) * | 2015-09-08 | 2021-07-12 | Childrens Hospital Philadelphia | Diagnosis and treatment of anxiety disorder |
US10918632B2 (en) * | 2016-09-07 | 2021-02-16 | The Children's Hospital Of Philadelphia | Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder |
-
2017
- 2017-09-06 US US16/330,469 patent/US10918632B2/en active Active
- 2017-09-06 WO PCT/US2017/050228 patent/WO2018048868A1/en unknown
- 2017-09-06 EP EP17785061.7A patent/EP3509640A1/en not_active Withdrawn
- 2017-09-06 CA CA3035971A patent/CA3035971A1/en not_active Abandoned
-
2021
- 2021-02-12 US US17/175,101 patent/US11779577B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CA3035971A1 (en) | 2018-03-15 |
US20210267958A1 (en) | 2021-09-02 |
US20190298706A1 (en) | 2019-10-03 |
US10918632B2 (en) | 2021-02-16 |
WO2018048868A1 (en) | 2018-03-15 |
US11779577B2 (en) | 2023-10-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11779577B2 (en) | Nonselective metabotropic glutamate receptor activators for treatment of anorexia nervosa and binge eating disorder | |
US11298347B2 (en) | Methods of diagnosing and treating Tourette syndrome | |
WO2008052167A2 (en) | Methods to identify patients at risk of developing adverse events during treatment with antidepressant medication | |
US20210137909A1 (en) | Methods of diagnosing and treating adhd in biomarker positive subjects |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20190405 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20210202 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20220413 |